细胞周期蛋白依赖性激酶CDK4/6过度活跃，是激素受体阳性乳腺癌内分泌治疗耐药主要原因之一，CDK4/6抑制剂可逆转耐药死循环，但是此类药物过去主要依靠进口。2021年，英国《自然医学》正式发表DAWNA-1研究报告，首次证实中国原创CDK4/6抑制剂达尔西利联合雌激素受体抑制剂氟维司群，二线治疗激素受体阳性晚期乳腺癌耐药患者有效，中位无进展生存延长1.8～2.2倍，进展或死亡风险降低55%～58%。那么，如果更早用药，将达尔西利用于一线治疗激素受体阳性晚期乳腺癌患者是否有效？ 2023年5月11日，英国《柳叶刀》肿瘤学分册在线发表中国工程院院士徐兵河、中国医学科学院肿瘤医院张频、哈尔滨医科大学附属肿瘤医院张清媛、天津医科大学肿瘤医院佟仲生、辽宁省肿瘤医院孙涛、吉林大学第一医院李薇、湖南省肿瘤医院欧阳取长、复旦大学附属肿瘤医院胡夕春、吉林省肿瘤医院程颖、河南省肿瘤医院闫敏、中国科学技术大学附属第一医院（安徽省立医院）潘跃银、中国医科大学附属第一医院滕月娥、四川大学华西医院鄢希、中山大学孙逸仙纪念医院汪颖、广西医科大学附属肿瘤医院谢伟敏、重庆大学附属肿瘤医院曾晓华、浙江省肿瘤医院王晓稼、安徽省肿瘤医院胡长路、河北医科大学第四医院耿翠芝、复旦大学附属中山医院张宏伟、内蒙古自治区人民医院李文新、湖北省肿瘤医院吴新红、广西医科大学第一附属医院钟进才、吉林大学第二医院徐景伟、中山大学肿瘤防治中心史艳侠、恒瑞医药韦文华、娜依玛·巴亚西、朱晓宇等学者的DAWNA-2研究报告，对达尔西利或安慰剂联合芳香化酶抑制剂一线治疗激素受体阳性晚期乳腺癌的有效性和安全性进行了比较。该研究由中国医学科学院创新基金和恒瑞医药资助。DAWNA-2 (NCT03966898): A Study of SHR6390 in Combination With Letrozole or Anastrozole in Patients With HR Positive and HER2 Negative Advanced Breast Cancer (A Phase III Study to Evaluate Efficacy and Safety of SHR6390 in Combination With Letrozole or Anastrozole Versus Placebo in Combination With Letrozole or Anastrozole in Patients With HR Positive and HER2 Negative Recurrent/Metastatic Breast Cancer) 该多中心随机双盲安慰剂对照三期临床研究于2019年7月19日至2020年12月25日从全国42家医院入组年龄18～75岁、无论是否绝经、体力状态评分为0～1、病理学证实激素受体阳性HER2阴性晚期乳腺癌尚未治疗患者456例，按2∶1的比例随机分为两组：其中303例每天口服达尔西利150毫克3周随后停1周，其余153例口服安慰剂。两组患者全部接受内分泌治疗，每天口服芳香化酶抑制剂来曲唑2.5毫克或阿那曲唑1毫克。随机分组采用交互式网络反馈系统，区组大小为6，并根据内脏转移、既往术后或术前内分泌治疗情况以及内分泌治疗用药进行分层。全部研究者、患者、资助者对分组情况设盲。主要终点为研究者评定的无进展生存，对符合入组标准接受随机分配的全部患者进行分析。对实际用药至少一次的患者进行药物安全性分析。预设优效界值为单侧对数秩P≤0.0076。该研究目前正在进行但是已经停止入组，本文为预先计划的中期分析。 结果，截至2022年6月1日，随访时间中位21.6个月，四分位18.3～25.9个月，达尔西利组303例患者与安慰剂组153例患者相比：- 中位无进展生存：延长12.4个月（30.6个月比18.2个月，95%置信区间：30.6～未达终点比16.5～22.5）
- 进展或死亡风险：降低49%（分层风险比：0.51，95%置信区间：0.38～0.69，单侧对数秩P<0.0001）
参考PALOMA-2、MONARCH-3、MONALEESA-2、MONALEESA-7研究结果，进口CDK4/6抑制剂哌柏西利、阿贝西利、瑞波西利分别将进展或死亡风险降低42%、45%、43%、45%。 对实际用药至少一次的患者进行药物安全性分析，达尔西利组302例患者与安慰剂组153例患者相比：- 治疗相关死亡事件发生率：0.66%（死因不明）比0
因此，该研究结果表明，对于激素受体阳性HER2阴性晚期乳腺癌尚未治疗患者，达尔西利联合来曲唑或阿那曲唑的利远大于弊，可以作为一线治疗新标准，成为现有治疗方案的替代选择之一。Lancet Oncol. 2023 May 11. IF: 54.433Dalpiciclib plus letrozole or anastrozole versus placebo plus letrozole or anastrozole as first-line treatment in patients with hormone receptor-positive, HER2-negative advanced breast cancer (DAWNA-2): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.Pin Zhang, Qingyuan Zhang, Zhongsheng Tong, Tao Sun, Wei Li, Quchang Ouyang, Xichun Hu, Ying Cheng, Min Yan, Yueyin Pan, Yuee Teng, Xi Yan, Ying Wang, Weimin Xie, Xiaohua Zeng, Xiaojia Wang, Changlu Hu, Cuizhi Geng, Hongwei Zhang, Wenxin Li, Xinhong Wu, Jincai Zhong, Jingwei Xu, Yanxia Shi, Wenhua Wei, Nayima Bayaxi, Xiaoyu Zhu, Binghe Xu.National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Harbin Medical University Cancer Hospital, Harbin, China; Tianjin Medical University Cancer Institute and Hospital, Tianjin, China; Liaoning Cancer Hospital and Institute, Shenyang, China; The First Hospital of Jilin University, Changchun, China; Hunan Cancer Hospital, Changsha, China; Fudan University Shanghai Cancer Center, Shanghai, China; Jilin Cancer Hospital, Changchun, China; Henan Cancer Hospital, Zhengzhou, China; First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, China; First Hospital of China Medical University, Shenyang, China; West China Hospital, Sichuan University, Chengdu, China; Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Guangxi Medical University Cancer Hospital, Nanning, China; Chongqing University Cancer Hospital, Chongqing, China; Zhejiang Cancer Hospital, Hangzhou, China; Anhui Provincial Cancer Hospital, Hefei, China; The Fourth Hospital of Hebei Medical University, Shijiazhuang, China; Zhongshan Hospital, Fudan University, Shanghai, China; Inner Mongolia Autonomous Region People's Hospital, Hohhot, China; Hubei Cancer Hospital, Wuhan, China; The First Affiliated Hospital of Guangxi Medical University, Nanning, China; The Second Hospital of Jilin University, Changchun, China; Sun Yat-sen University Cancer Center, Guangzhou, China; Jiangsu Hengrui Pharmaceuticals, Shanghai, China.BACKGROUND: Adding CDK4/6 inhibitor dalpiciclib to fulvestrant significantly prolonged progression-free survival in patients with hormone receptor-positive, HER2-negative advanced breast cancer progressing after endocrine therapy. We aimed to assess the efficacy and safety of dalpiciclib plus letrozole or anastrozole in patients with hormone receptor-positive, HER2-negative advanced breast cancer who had no previous systemic therapy in the advanced setting.METHODS: DAWNA-2 is a randomised, double-blind, placebo-controlled, phase 3 trial done at 42 hospitals in China. Eligible patients were aged 18-75 years, of any menopausal status, had an ECOG performance status of 0-1, and had pathologically confirmed hormone receptor-positive, HER2-negative untreated advanced breast cancer. Patients were randomly assigned (2:1) to receive oral dalpiciclib (150 mg per day for 3 weeks, followed by 1 week off) or matching placebo. Both groups also received endocrine therapy: either 2.5 mg letrozole or 1 mg anastrozole orally once daily continuously. Randomisation was using an interactive web response system (block size of six) and stratified according to visceral metastasis, previous endocrine therapy in the adjuvant or neoadjuvant setting, and endocrine therapy partner. All investigators, patients, and the funders of the study were masked to group allocation. We present the results of the preplanned interim analyses for the primary endpoint of investigator-assessed progression-free survival, which was assessed in all randomly assigned patients who met the eligibility criteria by intention-to treat. Safety was analysed in all randomly assigned patients who received at least one dose of study treatment. The superiority boundary was calculated as a one-sided p value of 0.0076 or less. This trial is registered with ClinicalTrials.gov, NCT03966898, and is ongoing but closed to recruitment.FINDINGS: Between July 19, 2019, and Dec 25, 2020, 580 patients were screened and 456 were eligible and randomly assigned to the dalpiciclib group (n=303) or placebo group (n=153). At data cutoff (June 1, 2022), median follow-up was 21.6 months (IQR 18.3-25.9), and 103 (34%) of 303 patients in the dalpiciclib group and 83 (54%) of 153 patients in the placebo group had disease progression or died. Median progression-free survival was significantly longer in the dalpiciclib group than in the placebo group (30.6 months [95% CI 30.6-not reached] vs 18.2 months [16.5-22.5]; stratified hazard ratio 0.51 [95% CI 0.38-0.69]; one-sided log-rank p<0.0001). Adverse events of grade 3 or 4 were reported in 271 (90%) of 302 patients in the dalpiciclib group and 18 (12%) of 153 patients in the placebo group. The most common adverse events of grade 3 or 4 were neutropenia (259 [86%] in the dalpiciclib group vs none in the placebo group) and leukopenia (201 [67%] vs none). Serious adverse events were reported for 36 (12%) patients in the dalpiciclib group and ten (7%) patients in the placebo group. Two treatment-related deaths occurred, both in the dalpiciclib group (deaths from unknown causes).INTERPRETATION: Our findings suggest that dalpiciclib plus letrozole or anastrozole could be a novel standard first-line treatment for patients with hormone receptor-positive, HER2-negative advanced breast cancer, and is an alternative option to the current treatment landscape.FUNDING: Jiangsu Hengrui Pharmaceuticals and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences.DOI: 10.1016/S1470-2045(23)00172-9
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